γ-hydroxybutyrates (GHBs), such as sodium γ-hydroxybutyrate (NaGHB, also known as sodium oxybate) and γ-hydroxybutyric acids, are used therapeutically to treat insomnia, depression, narcolepsy, and alcoholism, and are also used as anesthetics and hypnotics. GHBs are FDA approved to reduce the number of cataplexy attacks in patients with narcolepsy. For this treatment, NaGHB is typically administered as an oral solution containing about 0.5 g/mL NaGHB with a dosage range from 4.5 g per night to 9 g per night.
NaGHB is generally prepared by reacting γ-butyrolactone (GBL) with sodium hydroxide, typically under reflux conditions in an aqueous solution. (See, e.g., JACS1929, v. 51, p. 260). Established methods for preparing NaGHB typically result in only moderate yields, require extended reaction times, and/or require further recrystallization or processing steps. For example, U.S. Pat. No. 3,051,619 describes a process for preparing aqueous compositions of NaGHB involving prolonged heating of an aqueous mixture of GBL and NaOH, followed by subsequent recrystallization of NaGHB from alcohol.
German Pat. Nos. DD 237,308-237,310 describe the synthesis of NaGHB in water or water/alcohol mixtures by prolonged heating of an aqueous mixture of sodium hydroxide and GBL. While the use of alcohol/water mixtures avoids the additional recrystallization step, the process results in significantly less than quantitative yield, requires an alcohol wash of the product, and requires an evaporation/distillation step before the final product is isolated.
NaGHB drug products are typically formulated as an aqueous solution at or around neutral pH. Processes for preparing NaGHB drug formulations, however, require an additional pH adjustment step, after the initial preparation of an aqueous solution of NaGHB. For example, U.S. Pat. Nos. 6,472,431, 6,780,889, 7,262,219, and U.S. Patent Application Publication No. 20070270491, all to Cook et al., describe formulating solid NaGHB as a drug product by dissolving the solid in water, which results in a high pH solution, followed by adjusting the pH of the solution by addition of an acid to give an approximately neutral pH drug product.